Gulf War Veterans' Illness: Symptom Chronicity via Interactions of Diet andLifestyle Risk Factors with the Gut Microbiome

项目摘要/摘要 海湾战争退伍军人疾病(GWVI)呈现为一系列复杂的不同症状， 在海湾战争退伍军人被部署到海湾地区25年多后，他们一直在坚持。这套 症状如此广泛，它阻碍了诊断标准，因此，GWVI被认为是一种真正的疾病 从否认疾病的存在到使用诸如“无法解释的疾病”这样的术语进展缓慢 退伍军人病)和“多症状疾病”。医学研究所委员会关于海湾战争的最新报告 And Health(2016)得出结论，GWVI不是一种心身疾病，现在有足够的证据表明 得出结论：被部署到海湾战争与健康结果之间存在因果关系 与这种疾病有关。这个庄严的委员会注意到，在澄清方面进展甚微 与GWVI相关的复杂症状集背后的病理机制及其结果是， 似乎没有一种单一的机制可以解释海湾战争疾病中出现的多种症状，以及 在战后这么多年里，不太可能确定一个单一的决定性原因“(报告第3页)。 我们同意GWVI所有因素的单一原因是不太可能的，可能是单一的病理生理 可以影响GWVI的不同症状并解释其持久性的机制，以及 其机制是肠道微生物群的生态失调。该项目的总体目标是分析影响 海湾战争战剂对肠道共生细菌的影响，并确定这些相互作用是否会导致 细菌产生短链脂肪酸和其他生物活性小分子的变化 由肠道细菌产生。这些细菌发酵和代谢的产物产生了许多影响 包括中枢神经系统。小鼠将接受经过验证的GWVI小鼠模型的治疗 (溴化吡斯的明+氯菊酯)和肠道微生物组将通过16S rRNA测序进行分析 使用MiSeq平台。这些试剂对超临界脂肪酸生产的影响将用以下方法确定 液-质联用法。确认为GWVI Will症状的CNS和GI障碍 也要接受评估。此后，高脂饮食对微生物组和单链脂肪酸生产的影响将是 已评估。最后，提出了一个新的治疗目标，将测试饮食干预和粪便微生物区系。 转移它们在GWVI修饰的肠道微生物群中恢复平衡的能力，并减少CNS和 这种严重疾病的胃肠道症状。据预测，高脂肪饮食会放大海湾战争的影响 药物对微生物组和代谢组有影响，并会导致GWVI症状随时间而恶化。 下一代测序和尖端质谱学的应用将有助于填补空白 在我们对海湾战争特工如何影响肠脑轴线上的交流的理解中。这些研究 也可能通过饮食恢复肠道微生物群的平衡来揭示GWVI的新治疗靶点 和微生物区系转移干预。

Project Summary/Abstract Gulf War Veterans’ Illnesses (GWVI) presents as a complex constellation of diverse symptoms that have persisted in Gulf War Veterans more than 25 years after their deployment to the Gulf region. This set of symptoms is so broad, it baffles diagnostic criteria and as a result, consideration of GWVI as a bona fide illness has progressed slowly from denial of its existence to the use of such terms as “unexplained illnesses” (used by the VA) and “multisymptom illness”. The most recent report by the Institute of Medicine Committee on Gulf War and Health (2016) concludes that GWVI is not a psychosomatic condition and sufficient evidence now exists to conclude that a causal relationship exists between being deployed to the Gulf War and the health outcomes associated with this disorder. This august Committee noted that little progress has been made in elucidating the pathological mechanisms that underlie the complex symptom set associated with GWVI and as a result, “it does not appear that a single mechanism can explain the multitude of symptoms seen in Gulf War Illness, and it is unlikely that a single definitive causal agent will be identified this many years after the war” (p. 3 of report). We agree that a single cause for all elements of GWVI is unlikely, it is possible that a single pathophysiological mechanism that could influence the diverse symptoms of GWVI, and explain their persistence, and that mechanism is a dysbiosis in the gut microbiome. The broad objectives of this project are to analyze the effects of Gulf War agents on the commensal bacteria in the gut and to determine if these interactions result in changes in the bacterial production of short chain fatty acids (SCFAs) and other bioactive small molecules produced by gut bacteria. These products of bacterial fermentation and metabolism exert numerous effects throughout the body to include the CNS. Mice will be treated with a validated mouse model of GWVI (pyridostigmine bromide plus permethrin) and the gut microbiome will be analyzed via 16S rRNA sequencing using the MiSeq platform. The effects of these same agents on SCFA production will be determined using liquid chromatography-mass spectrometry. CNS and GI disorders that are confirmed symptoms of GWVI will also be assessed. Thereafter, the effects of a high fat diet on the microbiome and SCFA production will be evaluated. Finally, a new treatment aim is proposed that will test dietary intervention and fecal microbiota transfer for their ability to restore balance in the GWVI-modified gut microbiome and to diminish the CNS and GI symptoms of this serious disorder. It is predicted that a high fat diet will magnify the effects of Gulf War agents on the microbiome and the metabolome and cause a time-dependent worsening of GWVI symptoms. Together, the application of next generation sequencing and cutting edge mass spectrometry will help fill gaps in our understanding of how Gulf War agents influence communication along the gut-brain axis. These studies may also reveal new therapeutic targets for GWVI by restoring balance in the gut microbiome through dietary and microbiota transfer interventions.